AN2728, a new boron-based topical anti-inflammatory agent, inhibits phosphodiesterase 4 (IRC4P.611)

The novel boron-containing compound, AN2728, is being investigated in phase 3 trials for atopic dermatitis treatment. It exerts its anti-inflammatory effect by inhibiting phosphodiesterase-4 (PDE4), which catalyzes the breakdown of cAMP to AMP. AN2728 competes with cAMP to inhibit the PDE4B1-catalytic domain with Ki of 173±26 nM; thus AN2728 interacts at the enzyme-active site. The X-ray structure of PDE4B-catalytic domain with AN2728 and its structural relative AN2898 reveals that the boron atom interacts with the bimetal center and occupies a position in the catalytic site similar to that of the cAMP phosphate. AN2728 has good affinity across PDE4 gene products A-D. Its selective affinity for PDE4 is 4-10-fold greater than its affinity for PDE1, 2, 3A, 6, or 7B. It is inactive on PDE3B, 5, 7A1, and 8-11. AN2728 activity increases intracellular cAMP and activates PKA, followed by phosphorylation and negative regulation of various cytokine transcription factors. AN2728 inhibits production of specific cytokines with a pattern similar to that of other established PDE4 inhibitors and distinct from those of a glucocorticoid and calcineurin inhibitor. To investigate reactivity against other targets, AN2728 was tested against a set of 50 receptors and ligand-gated ion channels for inhibition at 10 µM. Inhibition was <25% for all receptors; thus, AN2728 is specific for PDE4 and appears to exert an anti-inflammatory effect through inhibition of inflammatory cytokine production.